The research focus of my group is to understand the mechanism of endothelial dysfunction in pulmonary hypertension. The objective of this work is to develop new therapeutic strategies for treatment of this disease. To achieve this we use data from proteomic, genomic and metabolomic screening of pulmonary hypertensive patient samples available in our Centre. This allows us to identify signalling mediators linked to endothelial dysfunction. We also manipulate the expression levels and activity of selected protein targets in cultured pulmonary vascular cells in order to verify their role in pulmonary vascular remodelling.
Drawing inspiration from advances in computer processing, our group together with the group of Professor Joshua Edel (Department of Chemistry, ICL), have produced pulmonary artery-ona-chip, a three dimensional model of a living, muscularised human lung blood vessel on a microchip.
The device contains a series of microscopic chambers separated by a thin porous membrane. Endothelial cells are grown on one side and smooth muscle cells on the other. Nutritious medium is continuously pumped over the endothelial cells, effectively mimicking the flow of blood inside a vessel. By taking blood and cells from pulmonary hypertensive patients, we aim to recreate disease conditions inside the microchip. The device also aims to create a highly controlled environment for multiple drug testing and reduce, or even eliminate, the experimental use of animals.
Our group was first to demonstrate that deficiency of oxygen and nitric oxide is a key factor in the disease process, inducing pulmonary endothelial barrier dysfunction and abnormal angiogenic responses as a result of an imbalance in the activation of actin cytoskeleton regulators, Rho GTPases: RhoA and Rac1.
We have recently identified another Rho GTPase, RhoB which is involved in pulmonary vascular remodeling. RhoB regulates actin polymerisation and the intracellular trafficking of growth factor receptors in pulmonary endothelial and smooth muscle cells. Prenylation (the addition of hydrophobic molecules, farnesyl or a geranyl-geranyl moiety to the C-terminal cysteine(s) of the target protein) of RhoB is required for its membrane localization and activation. Interrupting this process could be helpful in a clinical setting: we are currently investigating the use of prenylation inhibitors in the treatment of pulmonary hypertension.
Other projects centre around four main areas: (a) the role of chloride channel proteins (CLIC) in endothelial dysfunction in pulmonary hypertension; (b) therapeutic targeting of enzymes increasing nitric oxide bioavailability, DDAH; (c) role of neutrophils in pulmonary endothelial and smooth muscle activation and vascular remodelling in pulmonary hypertension; (d) endothelium-derived microparticles in pulmonary hypertension.
CLIC4 regulates angiogenic responses in human pulmonary artery endothelial cells. Cells were cultured in normoxic conditions or were exposed to hypoxia (2% oxygen) for 18 h. The cells were over expressing CLIC4 (AdCLIC4) or CLIC4 shRNA, as indicated; Matrigel tube assay. Bar=100 Âµm.
Pathways affecting RhoA activity in pulmonary vasculature (Wojciak-Stothard B Postgrad Med J. 2008 Jul;84(993):348-53)
Pulmonary Vascular Biology Group
Lucio Iannone; firstname.lastname@example.org
Lulwah Aldabbous; email@example.com
Lisa Storck (primary supervisor: Dr Ed Tate from Chemistry Department); firstname.lastname@example.org
Dr Vahitha Abdul-Salam; email@example.com
Dr Lucie Duluc ; firstname.lastname@example.org
If you are interested in joining my research group, please contact me by email (email@example.com ), enclosing a CV, short description of your research experience to date and proposed source of funding for your work (if applicable).
Professor Hans-Joachin Schnittler, Institute of Anatomy and Vacular Biology, Munster University, Germany, 2005
Dr James Leiper, MRC Clinical Sciences Centre, Imperial College London, DDAH, vascular biology, nitric oxide, 2006 - 2016
Professor Jane Mitchell, Department of Cardiothoracic Pharmacology, National Heart and Lung Institute, Imperial College, vascular biology, 2011 - 2016
Professor C Bernabeu, Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas (CSIC), and Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), 28040, Madrid, Spain., endoglin, vascular biology, 2014 - 2016
Professor John C Edwards, Department of Internal Medicine, St. Louis University, St. Louis MO, 2012 - 2016
Professor Kurt Stenmark, University of Colorado Denver Health Sciences Center, Aurora, 2012 - 2016
Professor Stuart Yuspa, Centre for Cancer Research, Bethesda, MD, USA, chloride intracellular channel proteins, 2012 - 2016
Mark Toshner, Pulmonary Vascular Diseases Unit, Papworth Hospital NHS Foundation Trust, Papworth, Everard Cambridge, United Kingdom, vascular biology, 2013 - 2017
Role of chloride intracellular channel protein 4 in pulmonary vascular remodeling, 10th World Congress for Microcirculation, Kyoto, Japan, 2015
International CLIC4 meeting guest lecture:, Centre for Cancer Research, Bethesda, MD, USA, 2015
Rho GTPases in the regulation of endothelial function, Nencki Institute, Polish Academy of Sciences, Warsaw, Poland, 2012
RhoB is the regulation of endothelial dysfunction in pulmonary hypertension. Cardiovascular Biology Seminars., Clinical School, Cambridge University, 2013
Rho GTPases in the regulation of pulmonary vascular function, 6th European Vascular Biology Meeting, 2011
Cardiovascule Medicine Seminar Series: Rho GTPases in endothelial responses to hypoxia, King's College London, 2006
Regulation of endothelial polarity and migration under shear stress, Cell Motility Club, LMCB, UCL, 2003
Vascular endothelium: Role in disease pathogenesis and as a terapeutic agent: Rho GTPases in the regulation of endothelial function, Imperial College London Vascular Biology Symposium, 2008
Rho GTpases in endotelial responses to hypoxia, Grover Conference on Pulmonary Circulation, Denver, Colorado, 2006
Hypoxia, ischaemia and infarction: An Update. Cellular mechanisms underlying hypoxic damage., Fellowship of Postgraduate Medicine. Medical Society of London., 2007
Research Student Supervision
Sindi,H, Therapeutic role of exosome-mediated gene delivery in pulmonary hypertension (PH)
Aldabbous,L, The Role of Neutrophil Extracellular Traps (NETs) in the pathogenesis of Pulmonary Hypertension (PH)
Iannone,L, ADMA METABOLISM AND CHRONIC HYPOXIA-INDUCED PULMONARY HYPERTENSION
Storck,L, Profiling Protein Prenylation Using a Quantitative Chemical Proteomics Approach
Mahomed,A, ROLE OF CHLORIDE INTRACELLULAR CHANNEL 4 IN THE REGULATION OF INFLAMMATORY RESPONSES IN PULMONARY VASCULAR ENDOTHELIUM
Topp,SF, The effect of Tipifarnib on VEGF-induced pulmonary endothelial angiogenesis
Belik,D, Endoglin+ endothelium-derived microparticles in endothelial dysfunction in pulmonary hypertension
Dagalan,D, Microparticles and endothelial dysfunction in pulmonary hypertension
Yixing,W, Role of RhoB in the Regulation of Pulmonary Endothelial Responses to Hypoxia
Redpath,A, cGMP in the regulation of pulmonary endothelial function
Panesar,J, The Role of NETs in Pulmonary Endothelial Dysfunction: a potential player in the pathogenesis of PH
Chohan,V, The effects of RhoB prenylation modification on pulmonary artery endothelial cells exposed to hypoxia
Dain,K, The role of Chloride Intracellular Channel 4 in the regulation of leukocyte adhesion to the pulmonary endothelium
Valencia,D, The role of chloride intracellular channel 4 in nuclear factor kappa B- mediated inflammation in Pulmonary Arterial hypertension
Thanighan,K, Potential therapeutic intervention for pulmonary hypertension — making cells talk to each other
Liu,WK, The role of RhoA-induced microparticles in the regulation of pulmonary endothelial function in vitro
Syed,A, RhoB in regulation of pulmonary endothelial cell responses to hypoxia